HDAC4

histone deacetylase 4

2 disorders 1 untyped 1 causative 2q37.3 gene with protein product

HGNC:14063 Monarch NCBI Gene 9759 ENSG00000068024 UniProt P56524 OMIM 605314

Previous symbols: BDMR. Aliases: KIAA0288, HDAC-A, HDACA, HD4, HA6116, HDAC-4.

Normal function · from ai-gene-review (P56524, commit 79fe13b38970) · AI-generated, not KB evidence

HDAC4 is a class IIa histone deacetylase that functions primarily as a transcriptional corepressor by bridging DNA-binding transcription factors (especially MEF2 family) to the enzymatically active HDAC3/NCoR/SMRT corepressor complex. Due to a Tyr->His substitution in the active site (H803 in human HDAC4), class IIa HDACs including HDAC4 have intrinsically weak deacetylase activity toward acetylated lysines. HDAC4 undergoes regulated nucleocytoplasmic shuttling controlled by phosphorylation at serine residues (S246, S467, S632) and subsequent 14-3-3 protein binding. When phosphorylated, HDAC4 is sequestered in the cytoplasm; dephosphorylation allows nuclear import where it can repress transcription. HDAC4 plays important roles in skeletal and cardiac muscle differentiation, neuronal function, and metabolic regulation.

HDAC4 functions primarily as a transcriptional corepressor by bridging DNA-binding transcription factors (especially MEF2) to the enzymatically active HDAC3/NCoR/SMRT complex. Due to a Tyr->His substitution in the active site (H803), HDAC4 has very weak intrinsic deacetylase activity and relies on the HDAC3/NCoR/SMRT complex for catalytic function.

molecular function: transcription corepressor activity · directly involved in: negative regulation of transcription by RNA polymerase II; negative regulation of gene expression, epigenetic · locations: nucleoplasm · in complex: histone deacetylase complex

HDAC4 binds to DNA-binding transcription factors including MEF2 family members (MEF2A, MEF2C, MEF2D), HIF-1alpha, Sp1, and others. This binding is central to its function as a transcriptional coregulator.

molecular function: DNA-binding transcription factor binding · directly involved in: negative regulation of myotube differentiation · locations: nucleoplasm

HDAC4 functions as a molecular scaffold/adaptor bridging transcription factors to the HDAC3/NCoR/SMRT corepressor complex. Class II HDACs regulate transcription by bridging enzymatically active complexes to transcription factors independently of intrinsic HDAC activity.

molecular function: molecular adaptor activity · locations: nucleoplasm

HDAC4 binds 14-3-3 proteins at phosphorylated serine residues (S246, S467, S632), which sequesters HDAC4 in the cytoplasm. This interaction regulates HDAC4 nucleocytoplasmic shuttling and is critical for its transcriptional regulatory function.

molecular function: 14-3-3 protein binding · locations: cytoplasm

In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

Disorder	Relationship	Where the gene appears
Neurodevelopmental Disorder with Central Hypotonia and Dysmorphic Facies	causative de novo	mechanism: HDAC4 14-3-3 Binding Site Missense Variant variant: HDAC4 c.731C>A p.(Thr244Lys); HDAC4 c.740A>G p.(Glu247Gly); HDAC4 c.742C>G p.(Pro248Ala); HDAC4 c.743C>T p.(Pro248Leu) animal model: HDAC4 3SA constitutive-nuclear mutant mouse (could not be generated); HDAC4-overexpressing proliferating mouse chondrocytes
2q37 Microdeletion Syndrome	untyped Candidate contributor within HDAC4-containing 2q37 deletions	mechanism: Partial contribution of HDAC4 haploinsufficiency

Identity from HGNC (snapshot 2026-10-01). Page layers are described in the gene pages documentation.